ArticleMolecular neurobiology2022
A Novel SCA3 Knock-in Mouse Model Mimics the Human SCA3 Disease Phenotype Including Neuropathological, Behavioral, and Transcriptional Abnormalities Especially in Oligodendrocytes.
Article in Molecular neurobiology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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29 citing papers in PubMed, 41 citations in OpenAlex.
- Atrophin-1 antisense oligonucleotide provides robust protection from pathology in a fully humanized DRPLA model.Molecular therapy. Nucleic acids · 2026Article
- Assessment of microexon-associated junction usage in Parkinson's disease and spinocerebellar Ataxia type 3.Frontiers in molecular neuroscience · 2026Article
- Ataxin-3 Overexpression via Adeno-associated Viral Vector Injection in the Primate Cerebellum: A Novel Model of Spinocerebellar Ataxia Type 3.Experimental neurobiology · 2025Article
- GABAergic neuronal dysfunction underlies tremor in spinocerebellar ataxia 3.Disease models & mechanisms · 2025Article
- Long-read sequencing identifies ATXN3 repeat expansions, and transcriptomics reveals disease progression biomarkers and druggable targets for spinocerebellar ataxia type 3.BMC neurology · 2025Article
- Progression of biological markers in spinocerebellar ataxia type 3: longitudinal analysis of prospective data from the ESMI cohort.The Lancet regional health. Europe · 2025Article
- Influence of ATXN2 intermediate CAG repeats, 9bp duplication and alternative splicing on SCA3 pathogenesis.Acta neuropathologica communications · 2025Article
- Mutant THAP11 causes cerebellar neurodegeneration and triggers TREM2-mediated microglial activation in mice.The Journal of clinical investigation · 2025Article
- Dysregulation of alternative splicing is a transcriptomic feature of patient-derived fibroblasts from CAG repeat expansion spinocerebellar ataxias.Human molecular genetics · 2025Article
- Dietary and lifestyle interventions for the management of hereditary ataxias.Frontiers in nutrition · 2025Review
- Genetic modeling of degenerative diseases and mechanisms of neuronal regeneration in the zebrafish cerebellum.Cellular and molecular life sciences : CMLS · 2024Review
- ATXN3: a multifunctional protein involved in the polyglutamine disease spinocerebellar ataxia type 3.Expert reviews in molecular medicine · 2024Review
- Widespread alternative splicing dysregulation occurs presymptomatically in CAG expansion spinocerebellar ataxias.Brain : a journal of neurology · 2024Article
- Blood levels of neurofilament light are associated with disease progression in a mouse model of spinocerebellar ataxia type 3.Disease models & mechanisms · 2023Article
- ATXN3 controls DNA replication and transcription by regulating chromatin structure.Nucleic acids research · 2023Article
- Blood neurofilament light chain levels are associated with disease progression in a transgenic SCA3 mouse model.bioRxiv : the preprint server for biology · 2023Article
- Myelinating Glia: Potential Therapeutic Targets in Polyglutamine Spinocerebellar Ataxias.Cells · 2023Review
- The Josephin domain (JD) containing proteins are predicted to bind to the same interactors: Implications for spinocerebellar ataxia type 3 (SCA3) studies usingFrontiers in molecular neuroscience · 2023Article
- Impaired interactions of ataxin-3 with protein complexes reveals their specific structure and functions in SCA3 Ki150 model.Frontiers in molecular neuroscience · 2023Article
- CatWalk XT gait parameters: a review of reported parameters in pre-clinical studies of multiple central nervous system and peripheral nervous system disease models.Frontiers in behavioral neuroscience · 2023Review
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Authors and funding
14 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Spinocerebellar ataxia type 3 is the most common autosomal dominant inherited ataxia worldwide, caused by a CAG repeat expansion in the Ataxin-3 gene resulting in a polyglutamine (polyQ)-expansion in the corresponding protein. The disease is characterized by neuropathological, phenotypical, and specific transcriptional changes in affected brain regions. So far, there is no mouse model available representing all the different aspects of the disease, yet highly needed for a better understanding of the disease pathomechanisms. Here, we characterized a novel Ataxin-3 knock-in mouse model, expressing a heterozygous or homozygous expansion of 304 CAACAGs in the murine Ataxin-3 locus using biochemical, behavioral, and transcriptomic approaches. We compared neuropathological, and behavioral features of the new knock-in model with the in SCA3 research mostly used YAC84Q mouse model. Further, we compared transcriptional changes found in cerebellar samples of the SCA3 knock-in mice and post-mortem human SCA3 patients. The novel knock-in mouse is characterized by the expression of a polyQ-expansion in the murine Ataxin-3 protein, leading to aggregate formation, especially in brain regions known to be vulnerable in SCA3 patients, and impairment of Purkinje cells. Along these neuropathological changes, the mice showed a reduction in body weight accompanied by gait and balance instability. Transcriptomic analysis of cerebellar tissue revealed age-dependent differential expression, enriched for genes attributed to myelinating oligodendrocytes. Comparing these changes with those found in cerebellar tissue of SCA3 patients, we discovered an overlap of differentially expressed genes pointing towards similar gene expression perturbances in several genes linked to myelin sheaths and myelinating oligodendrocytes.
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